The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMC.

1Department of Pharmacology and Therapeutics, The University of Liverpool, UK. neill.liptrott@liv.ac.uk

Abstract

BACKGROUND AND PURPOSE:

The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on the expression of CYPs, transporters and chemokine receptors in PBMC.

KEY RESULTS:

We show here functional activity of CYP3A4 and CYP2B6 in PBMC. Furthermore, cytokines had a significant impact on the mRNA and protein expression of all proteins. For example, interleukin-2 (IL-2) had a marked impact on ABCB1 mRNA (% control 4745 +/- 11961) and protein (% control 200 +/- 57). Increases in drug efflux transporter expression, in response to cytokines, resulted in reduced cellular accumulation of digoxin [decrease of 17% and 26% for IL-2 and interferon-gamma (IFNgamma) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFNgamma respectively). The degree to which drug transporter and chemokine receptor expression changed in response to cytokines was positively correlated (e.g. ABCB1 and CXCR4, r(2) = 0.545).

CONCLUSIONS AND IMPLICATIONS:

These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells.

Impact of cytokine incubation on the intracellular accumulation of digoxin and saquinavir in PBMC from healthy volunteers. The impact of incubation with IL-2 and IFNγ on the cellular accumulation ration of (A) digoxin and (B) saquinavir was determined at both 0 and 24 h time points (n = 3). CTL, control; IFN, interferon; IL, interleukin; PBMC, peripheral blood mononuclear cells.